QD 


NRLF 


EXCHANGE 


A  Study  of  the  Hoesch  Reaction 


BY 

WILSON  DAVIS  LANGLEY, 
B.  S.  Wesleyan  University,  1918 
M.  S.  Wesleyan  University,  1919 


THESIS 

bmitted  in  partial  fulfillment  of  the  requirements  for  the  degree  of 
Doctor  of  Philosophy  in  Chemistry  in  the  Graduate  School 
of  the  University  of/Illinois,  1922 


Reprinted  from  the  Journal  of  the  American  Chemical  Society 
Vol.  XLVI,  No.  10.     October,  1922 


A  Study  of  the  Hoesch  Reaction 


BY 

WILSON  DAVIS  LANGLEY, 
B.  S.  Wesley  an  University,  1918 
M.  S.  Wesleyan  University,  1919 


THESIS 

*          •  .  ; 

Submitted  in  partial  fulfillment  of  the  requirements  for  the  degree  of 

Doctor  of  Philosophy  in  Chemistry  in  the  Graduate  School 

of  the  University  of  Illinois,  1922 


Reprinted  from  the  Journal  of  the  American  Chemical  Society 
Vol.  XLVI,  No.  10.     October,  1922 


•XC MANGA 


[Reprinted  from  the  Journal  of  the  American  Chemical  Society, 
Vol.  XLVI,  No.  10.      October,  1922.] 


[CONTRIBUTION  FROM  THE  CHEMICAL  LABORATORY  OP  THE  UNIVERSITY  OF  ILLINOIS] 

CONDENSATION  OF  CERTAIN  NITRILES  AND  VARIOUS  POLY- 
HYDROXYPHENOLS  TO  FORM  PHENOLIC  ACIDS 

BY  WILSON  D.  LANGLEY  WITH  ROGER  ADAMS' 

Received   July   10,   1922 

From  the  time  Hoesch2  first  discovered  that  nitriles  reacted  with  certain 
phenols  in  the  presence  of  anhydrous  zinc  chloride  and  dry  hydrogen  chlor- 
ide to  give  ketones  according  to  the  following  equations 

RCN 


ZnCl2-fHCl        1^/JC(=NH-HC1)R 


this  reaction  has  been  applied  extensively  in  organic  chemistry.  It  has 
proved  of  particular  value  in  the  synthesis  of  various  natural  products, 
in  the  preparation  of  certain  synthetic  drugs,  in  the  formation  of  coumar- 
anones,  and  various  other  types  of  ketones  and  aldehydes.* 

Another  application  of  this  reaction,  namely,  the  condensation  of  0- 
chloro-propionitrile  with  resorcinol  to  prepare  7-hydroxychromanone-4 
was  tried  as  follows: 

1  This  communication  is  an  abstract  of  a  thesis  submitted  by  W.  D.  Langley  in 
partial  fulfilment  of  the  requirements  for  the  degree  of  Doctor  of  Philosophy  in  Chemistry 
at  the  University  of  Illinois. 

2  Hoesch,  Ber.,  48,  1122  (1915). 

8  (a)  Hoesch,  ibid.,  50,  462  (1917).  (b)  Sonn,  ibid.,  50,  1262  (1917);  (c)  51,  821. 
1829  (1918);  (d)  52,  923  (1919).  (e)  Stephen,  J.  Chem.  Soc.,  117,  309,  (f)  1529  (1920), 
(g)  Karrer,  Helvetica  Chim.  Ada,  2,  89,  462,  486  (1919);  3,  261,  392,  541  (1920);  4, 
203,  707  (1921).  (h)  Fischer,  Ber.,  50,  611,  693  (1917).  (i)  Bauer,  Arch.  Pharm.,  259, 
53  (1921). 


CONDENSATION  OF  NITRIDES  AND  PHENOLS 
HOr"  "^OH  C1CH2CH2CN 


ZnCl2  +  HC1         ^  ^C(  =  NH-HC1)  H2O 
CH2CH2C1 


HO/\/°\ 

L.H2 

k    ;COCH2CH2C1 


from  which  by  treatment  with  butyl  nitrite  and  acid  the  compound  3,7- 
dihydroxychromone-4  would  be  produced.  This  compound  with  alcoholic 
sodium  hydroxide  should  give  fisetol. 


/\/°\ 
H0    Y     C 


H  HO/NOR 

rj,       COH  —  > 

II 

o 

The  initial  reaction,  however,  did  not  take  place  as  expected  and  the 
results  of  the  abnormal  reaction  are  reported  in  this  communication. 

The  condensation  of  j3-chloro-propionitrile  with  resorcinol  takes  place 
smoothly.  The  final  product  is  not  a  ketone  but  an  acid,  /3-(2,4-dihydroxy- 
phenyl)propionic  acid  (III).  The  formation  of  analogous  compounds 
takes  place  when  resorcinol  monomethyl  ether,  orcinol  or  phloroglucinol 
is  used;  in  the  cases  of  orcinol  or  phloroglucinol  unstable  acids  are  pro- 
duced which  immediately  decompose  into  water  and  the  corresponding 
lactones.  In  no  instance  during  these  experiments,  however,  was  the 
formation  of  any  ketone  observed.  This  is  a  surprising  type  of  reaction 
in  view  of  the  fact  that  chloro-acetonitrile  condenses  normally  with  re- 
sorcino!3b  as  follows. 


H    C1CH2CN     HOf  V>H 


ZnCl2  +  HC1        \y  C(  =  NH-HC1)CH*C1 

HO/NOH  HO/V-  0\ 

— >  >CH2 

L/COCH,C1  \/~ C 

There  have  already  been  described  in  the  literature  other  types  of  ni- 
triles  which  condense  abnormally  with  resorcinol  in  the  presence  of  hydro- 
gen chloride  and  zinc  chloride.  E.  Fischer  discovered  that  cinnamo- 


2322 


WESSON  D.  BANGLE  Y  WITH  ROGER  ADAMS 


nitrile  and  certain  substituted  cinnamonitriles  condense  with  phloro- 
glucinol,3h  not  as  would  be  expected,  but  instead  to  give  the  corresponding 
substituted  chromanones  according  to  the  following  equation, 


C6H6CH  =  CHCN 


=  NH-HCl 
H2 


OH 


H20 


CH2 


a  reaction  which  is  very  similar  to  that  observed  in  this  research.  Fischer 
assumed  as  a  mechanism  for  this  reaction  that  the  phloroglucinol  first 
adds  to  the  unsaturated  nitrile  and  that  the  hydrogen  chloride  then  con- 
verts the  nitrile  produced  into  the  imide  lac  tone  which  in  turn  is  readily 
hydrolyzed  to  the  lactone.  This  mechanism  seems  unlikely  in  view  of  the 
observations  made  with  /3-chloro-propionitrile.  It  is  well  known  that  un- 
saturated nitriles  add  halogen  acid4  with  great  ease  so  that  the  primary 
reaction  with  cinnamonitrile  is  undoubtedly  the  addition  of  hydrogen 
chloride.  There  will  thus  be  produced  a  0-chloro-propionitrile  derivative 
and  the  subsequent  mechanism  will  undoubtedly  be  similar  to  that  observed 
with'  /3-chloro-propionitrile  itself. 

When  the  /3-chloro-propionitrile  is  condensed  with  resorcinol  in  an- 
hydrous ether  in  the  presence  'of  hydrogen  chloride,  a  white  solid  slowly 
separates.  This  is  difficult  to  purify,  contains  both  chlorine  and  nitrogen, 
and  probably  has  •  Structure  I. 


NH-HC1 


H2O 


/. 

H(y\OH 

H2CH2COH2 


III 


When  I  is  treated  with  cold  water,  it  dissolves  completely,  and  within 
about  a  minute  an  oil  separates  which  on  cooling  solidifies.  This  is  the 
lactone,  II,  and  is  formed  in  practically  quantitative  yields.  The  structure 
of  this  lactone  is  certain,  as  shown  by  a  direct  synthesis  from  umbelli- 
ferone,  the  corresponding  unsaturated  lactone.  Upon  heating  either  the 
lactone  or  the  imide  hydrochloride  with  water,  the  corresponding  /3-(2,4- 
dihydroxyphenyl)propionic  acid  (III)  is  obtained. 

There  are  two  possible  mechanisms  by  which  these  substances  might 
be  formed. 


4  Moureu,  Bull.  soc.  chim..  27,  901  (1920). 


CONDENSATION  OF  NITRII^S  AND  PHENOLS  2323 

HO/NoH 
A  *       1VJCH2CH2CN 


HYY°^  =  NH.HC1 
HO/No— C(=NH-HC1)  f  ^H2 

I    J.       CH2CH2C1  X^\C^/ 

V  H2 

iv  n 

At  first  Mechanism  B  might  seem  the  more  likely  since  Stephen35  has 
presented  evidence  that  the  mechanism  of  the  reaction  of  nitriles  with 
resorcinol  to  give  ketones  is  first  a  condensation  of  the  cyano  group  with 
the  phenolic  hydroxyl  group  yielding  a  structure  similar  to  that  in  (IV), 
then  rearrangement  of  the  group  into  the  ring,  and  finally  hydrolysis. 
If  such  a  primary  mechanism  is  assumed  in  the  case  at  hand,  it  is  necessary 
merely  to  suppose  that  in  Compound  IV  the  reaction  of  the  chlorine 
attached  to  the  carbon  atom  with  the  hydrogen  in  the  ortho  position  in  the 
benzene  ring  to  eliminate  the  halogen  acid  and  to  form  a  ring  structure, 
has  a  greater  tendency  to  take  place  than  the  rearrangement  of  the  —  C 
(  =  NH  -HC1)CH2CH2C1  group  from  the  oxygen  to  the  ortho  carbon  atom, 
and  then  the  formation  of  a  ring.  This  mechanism  B,  is  shown  to  be  in- 
correct, however,  since  it  is  possible  in  the  case  of  the  condensation  of 
/3-chloro-propionitrile  with  resorcinol  monomethyl  ether  to  isolate  a  nitrile  V. 
The  formation  of  such  an  intermediate  excludes  the  possibility  of  the  pri- 
mary formation  of  Compound  IV,  and  is  strong  evidence  for  Mechanism  A. 

The  condensation  of  j8-chloro-propionitrile  with  resorcinol  does  not  take 
place  in  the  presence  of  anhydrous  zinc  chloride  alone.  From  this  it  might 
be  concluded  that  the  hydrogen  chloride  which  must  be  present  for  the 
condensation  to  take  place  first  reacts  with  the  0-chloro-propionitrile  to 
give  a  chloro-imide  and  that  this  resulting  compound  condenses  with  the 
resorcinol.  The  fact  that  the  condensation  takes  place  slowly  in  the  pres- 
ence of  hydrogen  chloride  alone  is  further  evidence  for  this  mechanism. 
However,  conclusive  proof  that  the  correct  mechanism  is  presented  by 
Mechanism  A  is  afforded  in  the  condensation  with  resorcinol  monomethyl 
ether,  by  the  isolation  of  the  nitrile,  V. 

The  condensation  of  resorcinol,  orcinol  and  phloroglucinol  with  acrylic 
nitrile  also  runs  smoothly  and  yields  the  same  phenolic  lactones  or  acids 
as  are  produced  by  using  /3-chloro-propionitrile. 

It  seemed  possible,  since  the  chlorine  in  the  0  position  to  a  cyano  group 
reacts  so  readily  with  resorcinol,  that  the  chlorine  in  #-chloro-propionic 
ester,  or  even  that  the  halogen  in  such  compounds  as  allyl  bromide,  or 
trimethylene  bromide  might  also  condense  under  the  same  conditions. 


2324  WILSON  D.  I,ANGl,8Y  WITH  ROGER  ADAMS 

However,  it  is  impossible  to  cause  any  condensation  with  these  substances, 
thus  indicating  that  the  cyano  group  undoubtedly  plays  an  important 
part  in  the  reaction. 

An  attempt  was  also  made  to  condense  /3-chloro-propionitrile  with 
phenol  in  presence  of  zinc  chloride  and  hydrogen  chloride,  but  no  reaction 
occurred. 

More  surprising  is  the  fact  that  7-chloro-butyronitrile  also  reacts  ab- 
normally with  resorcinol  to  give  2  unstable  intermediate  compounds  which 
hydrolyze  to  7- (2,4-dihydroxyphenyl) butyric  acid,  VI. 


O 

TT/*k/\/ 

CHgO/NoH  HO/NOH 


HO|       I       C  =  NH-HC1 


CHa 


njw         njn  nui       JWXT 

IJcHaCHaCN  lJcH,CH2CH,CO,H  V/V/ 

CHCH, 
V  VI  VII 

The  compound  which  is  obtained  directly  from  the  original  reaction  mix- 
ture, is  probably  the  chloro-imide  hydrochloride.  Upon  washing  with 
water,  it  is  converted  into  a  compound  containing  less  chlorine,  perhaps 
a  chloro-imide,  which  by  contact  with  water  for  a  longer  time  is  hydro- 
lyzed  to  the  acid.  The  intermediate  compounds  were  difficult  to  obtain 
pure  so  that  their  structure  was  not  definitely  established.  The  yields 
are  lower,  to  be  sure,  than  in  the  case  of  the  £-jchloro-propionitrile-resorcinol 
condensation;  nevertheless,  the  reaction  takes  place  with  comparative 
ease  and  apparently  gives  no  product  in  which  the  cyano  group  condenses 
directly  with  the  ring  to  give  a  ketone.  The  reaction  of  7-chloro-butyro- 
nitrile with  orcinol  or  phloroglucinol  does  not  go  readily  and  no  well  de- 
fined products  were  isolated. 

The  constitution  of  Compound  VI  from  7-chloro-butyronitrile  and  re- 
sorcinol was  proved  by  analysis,  and  by  the  fact  that  it  does  not  form  the 
corresponding  lactone  under  the  same  conditions  as  does  j8-  (2,4-dihydroxy- 
phenyl) propionic  acid.  This  fact  excludes  the  possibility  that  7-chloro- 
butyronitrile  undergoes  a  transformation  before  reacting  with  the  resorci- 
nol, namely  the  elimination  and  re-addition  of  hydrogen  chloride  to  give 
/3-chloro-butyronitrile,  which  then  would  condense  to  give  /3-methyl 
/3- (2,4-dihydroxyphenyl) propionic  acid  lactone  imide  hydrochloride,  VII. 

An  attempt  was  made  to  condense  ethylene  cyanohydrin  with  resorcinol, 
but  only  a  small  amount  of  0-  (2,4-dihydroxyphenyl)  propionic  acid  was  ob- 
tained from  the  reaction  mixture.  If  any  ketone  was  formed,  it  could  not 
be  isolated.  The  reaction  does  not  run  smoothly  and  this  is  probably  due 
to  the  molecule  of  water  which  must  necessarily  be  eliminated  in  the  re- 
action. It  is  interesting,  however,  that  the  cyanohydrin  of  acetaldehyde 
condenses  normally  with  resorcinol.36 


CONDENSATION  OP  NITRIDES  AND  PHENOLS  2325 

Experimental 

jS-Chloro-propionitrile,  C1CH2CH2CN. — This  substance  was  prepared  according 
to  the  method  of  Henry5,  by  the  action  of  phosphorus  pentachloride  on  ethylene  cyano- 
hydrin.  The  reaction  was  carried  out  in  toluene  suspension  in  preference  to  no  solvent. 
For  successful  results  in  the  following  experiments,  the  product  must  be  pure.  After 
being  freed  as  thoroughly  as  possible  from  phosphorus  oxychloride  by  fractionation  in  a 
vacuum  (20-25  mm.),  the  /3-chloro-propionitrile  fraction  boiling  at  65-72°  at  20  mm.  was 
poured  carefully  into  cold  water  and  shaken,  the  temperature  being  kept  low.  The 
oily  nitrile  was  separated,  washed  with  sodium  carbonate  solution,  then  with  water, 
dried  over  anhydrous  sodium  sulfate,  and  finally  purified  by  distillation  in  a  vacuum. 

Acrylic  Nitrile,  CH2  =  CHCN. — This  substance  was  prepared  by  the  method  of 
Moureu.4 

7-Chloro-buryronitrile,  C1CH2CH2CH2CN. — This  was  prepared  from  trimethylene 
chlorobromide  and  sodium  cyanide  according  to  the  method  of  Gabriel.6 

OHf 
/3-(2,4-Dihydroxyphenyl)propionic  Acid  . — In  a  2-liter  round- 


bottom  flask  protected  with  a  calcium  chloride  tube  were  placed  130  g.  of  c.  P. 
resorcinol,  90  g.  of  pure  /3-chloro-propionitrile  and  700  cc.  of  dry  ether.  To  this  solution 
was  added  40  g.  of  zinc  chloride  which  had  been  freshly  fused  and  then  powdered,  and 
dry  hydrogen  chloride  was  passed  in  as  long  as  there  was  any  absorption.  The  flask  was 
then  tightly  stoppered  and  alloVed  to  stand  overnight.  Dry  hydrogen  chloride  was 
again  slowly  passed  in  for  5  hours  and  the  flask  was  allowed  to  stand  for  36  hours  longer. 
The  mass  of  crystals  which  separated  was  sticky  and  hard  to  handle  due  to  the  presence 
of  zinc  chloride  but  was  filtered  from  the  red  solution  and  washed  with  dry  ether.  The 
original  filtrate  was  again  stoppered  and  allowed  to  stand  for  48  hours,  during  which  38  g. 
more  of  solid  formed.  After  filtering  and  allowing  the  filtrate  to  stand  for  a  week  longer, 
25  g.  more  of  crystals  was  produced. 

The  total  quantity  of  crystals  was  dissolved  in  450  cc.  of  water  and  heated  on  a 
steam-bath  for  4  hours.  An  oily  layer  of  /3-(2,4-dihydroxyphenyl)propionic  acid  lactone 
first  separated  which,  if  cooled,  solidified.  The  layer  however,  was  not  removed,  but 
the  reaction  mixture  was  heated  further,  thus  causing  the  lactone  to  go  gradually  into 
solution.  After  this  had  cooled  and  stood  for  some  hours,  86.5  g.  of  /3-(2,4-dihydroxy- 
phenyl)propionic  acid  crystallized  and  was  filtered.  The  aqueous  filtrate,  upon  evapora- 
tion in  a  vacuum  to  175  cc.  and  cooling,  yielded  a  second  crop  of  crystals  which  weighed 
22.5  g.  Further  concentration  and  cooling  of  the  filtrate  yielded  only  inorganic  salts. 
The  total  yield  of  product  was  thus  109  g.  (56%).  The  substance  was  almost  always 
light  brown  and  this  color  was  difficult  to  remove  even  though  several  crystallizations 
from  water  and  bone  black  were  made.  The  substance  always  separated  from  the  aque- 
ous solution  very  slowly.  In  spite  of  the  color,  the  product  melted  sharply  at  165°  with 
decomposition,  the  same  point  as  pure  white  material  obtained  by  hydrolysis  of  the  pure 
lactone. 

Analyses.  Subs.,  0.3679:  CO2,  0.7967;  H2O,  0.1799.  Subs.,  0.2973:  24.24  cc.  of 
0.0717  N  NaOH.  Calc.  for  C9Hi0O4:  C,  59.34;  H,  5.49;  neut.  equivi,  182.  Found: 
C,  59.05;  H,  5.43;  neut.  equiv.,  171. 

This  substance  was  prepared  by  Hlasiwetz7  by  the  reduction  of  umbelliferone,  but 
he  stated  that  the  acid  decomposed  when  heated  above  110°.  In  order  to  make  certain 

6  Henry,  Bull.  acad.  roy.  med.  Belg.,  [3]  35,  360  (1898). 
•  Gabriel,  Ber.,  23,  1771  (1890). 

7  Hlasiwetz,  Ann.,  139.  102  (1866). 


2326  WIIvSON  D.  LANGLEY  WITH  ROGER  ADAMS 

that  the  compound  which  was  obtained  in  this  investigation  had  the  structure  assigned 
to  it,  umbelliferone  was  made  by  the  action  of  malic  acid  upon  resorcinol  by  means  of 
cone,  sulfuric  acid.  The  product  was  carefully  purified  and  then  reduced  with  sodium 
amalgam  as  described  by  Hlasiwetz.  Upon  acidification  with  hydrochloric  acid,  red 
crystals  formed,  which  were  boiled  with  bone  black  in  water  solution,  and  filtered. 
Nearly  colorless  crystals  melting  at  165°  were  obtained  which,  when  mixed  with  /3-(2,4- 
dihydroxyphenyl)propionic  acid,  melted  at  the  same  temperature  as  when  alone.  For 
further  confirmation,  another  sample  of  the  acid  was  treated  with  excess  of  acetic  anhy- 
dride and  boiled  for  20  minutes.  The  reaction  mixture  was  poured  into  water  to  de- 
compose the  excess  of  anhydride,  and  the  brown  solid  which  separated  was  filtered, 
washed  and  crystallized  from  20%  methyl  alcohol.  A  white  powder,  the  acetate  of 
dihydro-umbelliferone,  [/?-(2-hydroxy-4-acetoxyphenyl)  propionic  acid  lactone],  was  thus 
produced  which  melted  at  112°  and  proved  to  be  identical  with  the  compound  prepared 
by  the  action  of  acetic  anhydride  on  ]3-(2,4-dihy  droxyphenyl)  propionic  acid  made  from 
resorcinol  and  8-chloro-propionitrile. 

/3-(2,4-Dihydroxyphenyl)propionic  acid  may  also  be  made  by  the  action  of  acrylic 
nitrile  upon  resorcinol.  A  solution  of  12  g.  of  resorcinol  and  6  g.  of  acrylic  nitrile  in  70 
cc.  of  dry  ether  was  treated  with  4  g.  of  freshly  fused  and  powdered  zinc  chloride,  after 
which  dry  hydrogen  chloride  was  passed  in  until  the  solution  was  saturated.  At  the 
end  of  12  hours,  a  heavy  white  crystalline  product  had  formed.  The  ether  was  decanted 
and  a  small  portion  of  the  solid  treated  directly  with  water.  There  was  thus  produced 
/3-(2,4-dihy  droxyphenyl)  propionic  acid  lactone,  which  melted  at  133-134°,  and  proved 
to  be  identical  with  the  substance  prepared  from  resorcmol  and  /3-chloro-propionitrile. 

The  remainder  of  the  solid  was  boiled  with  50  cc.  of  water  for  a  half  hour,  and  then 
allowed  to  stand.  Crystals  separated  which  proved  to  be  0-(2,4-dihydroxyphenyl)- 
propionic  acid. 


/3-(2,4-Dihydroxyphenyl)  propionic  Acid  Lactone,  CH     .  —  /3-(2,4-Dihy- 

c 
H2 

droxyphenyl)  propionic  acid  was  heated  in  an  oven  at  130-135°  for  2  hours.  The 
melt  which  formed  was  allowed  to  cool  and  the  product  then  crystallized  from 
toluene.  White  cubical  crystals  resulted  which,  upon  complete  purification  melted  at 
132-133°.  This  substance  is  identical  in  all  respects  with  that  obtained  by  the  treat- 
ment of  the  original  reaction  product  of  resorcinol  and  0-chloro-propionitrile  with  cold 
water. 

Analyses.  Subs.,  0.1560:  CO2,  0.3795;  H2O,  0.0072.  .Calc.  for  C9H8O8:  C,  65.85; 
H,  4.88.  Found:  C,  66.33;  H,  4.96. 

The  substance  was  insoluble  in  sodium  carbonate  until  the  solution  was  heated, 
when  it  dissolved.  Upon  acidification  with  acid  ^-(2,4-dihydroxyphenyl)  propionic  acid 
gradually  deposited  in  the  form  of  hard  crystals. 


/3-(2-Hydroxy-4-acetoxyphenyl)  propionic  Acid  Lactone, 

c/ 
H2 

A  solution  of  7  g.  of  /3-(2,4-dihy  droxyphenyl)  propionic  acid  in  10  g.  of  acetic  anhydride 
was  heated  on  a  water-bath  for  an  hour.  A  red  solution  was  produced  ;  this  was  cooled 
and  then  poured  into  70  cc.  of  cold  water  when  a  yellow  crystalline  solid  separated 


CONDENSATION  OF  NITRIDES  AND  PHENOLS  2327 

which  weighed  9  g.     Upon  crystallization  from  20%  methyl  alcohol  the  substance  was 
readily  obtained  pure  and  formed  white  crystals  melting  at  111-112°. 

Analyses.  Subs.,  0.3116,  0.3278:  CO2,  0.7382,  0.7742;  H2O,  0.1357,  0.1387. 
Calc.  for  CuHio04:  C,  64.1;  H,  4.89.  F^und:  C,  64.63,  64.40;  H,  4.83,  4.67. 

It  was  insoluble  in  sodium  carbonate  until  heated.  Upon  hydrolysis  either  with 
sodium  carbonate  or  water,  /3-(2,4-dihydroxyphenyl)propionic  acid  resulted. 


£-(2,4-Dimethoxyphenyl)propionic  Acid,  .  —  A  solution  of 


35  g.  of  /3-(2,4-dihydroxyphenyl)propionic  acid  in  100  cc.  of  10%  sodium  hydroxide 
was  treated  with  36  g.  of  dimethyl  sulfate.  The  mixture  was  thoroughly  shaken  for 
some  minutes  and  then  heated  on  a  water-bath  under  a  reflux  condenser.  After  the 
initial  reaction  had  taken  place,  100  cc.  more  of  10%  sodium  hydroxide  solution  and  35  g. 
of  dimethyl  sulfate  were  added  and  the  mixture  was  again  heated  until  the  dimethyl 
sulfate  was  completely  decomposed.  Upon  cooling  the  reaction  mixture  and  acidifying 
with  hydrochloric  acid,  needle-like  crystals  separated.  The  yield  was  28.5  g.  (68%). 
It  was  readily  purified  by  crystallization  from  water  and  then  melted  at  102.5-103.5°. 

Analyses.  Subs.,  0.2991:  CO2,  0.6896;  H2O,  0.1739.  Subs.,  0.1260:  8.7  cc.  of 
0.0717  N  NaOH.  Calc.  for  CuH14O4:  C,  62.8;  H,  6.6;  neut.  equiv.,  210.  Found: 
C,  62.87;  H,  6.5;  neut.  equiv.,  201. 

This  substance  is  without  doubt  the  same  as  that  prepared  by  W.  Will8  by  the  re- 
duction of  dimethoxy-umbellic  acid.  He  reported  the  melting  point  as  105°. 


0-(5-Nitroso-2,4-dihydroxyphenyl)propionic  AcidLactone, 

N\C/ 

H2 

A  solution  of  3  g.  of  /3-(2,4-dihydroxyphenyl)propiomc  acid  in  50  cc.  of  alcohol  was  treated 
with  4  g.  of  freshly  distilled  butyl  nitrite.  The  flask  was  then  cooled  and  10  cc.  of  cone. 
hydrochloric  acid  added.  Fumes  of  nitrogen  dioxide  were  evolved,  heat  was  generated, 
and  a  red  precipitate  was  formed.  An  additional  40  cc.  of  cone,  hydrochloric  acid  was 
then  added  and  the  flask  allowed  to  stand  for  about  30  minutes.  The  solid  was  filtered, 
washed  twice  with  cold  water,  and  dried.  The  yield  was  4  g.  The  crude  material 
varied  in  color  in  different  experiments  from  a  cream  color  to  red,  and  upon  exposure  to 
air  it  generally  turned  green.  The  crude  substance  was  purified  by  dissolving  4  g.  in 
70  cc.  of  boiling  water,  filtering  hot  and  allowing  to  cool.  In  spite  of  the  fact  that  the 
aqueous  solution  was  green,  a  cream-colored  solid  separated.  Upon  filtering,  washing 
and  drying  over  sulfuric  acid  in  a  vacuum  desiccator,  the  product  did  not  change  color 
and  melted  sharply  at  147.5-148°,  with  decomposition. 

Analysis.     Subs.,  0.1873:    N2,  13.1  cc.  (26°  and  737  mm.).     Calc.  for  C9H7O4N: 
N,  7.25.     Found:   7.61. 

This  substance  could  not  be  formed  by  treatment  of  0-(2,4-dihydroxyphenyl)- 
propionic  acid  lactone  with  butyl  nitrite,  but  had  to  be  prepared  from  the  acid. 

CH3O/NOH 
j8-(2-Hydroxy-4-methoxyphenyl)propionic  Acid, 


A  mixture  of  30  g.  of  resorcinol  monomethyl  ether  and  22  g.  of  /S-chloro-propionitrile 
8  Will,  Ber.,  16,  2116  (1883). 


2328  WILSON  D.  LANGLEY  WITH  ROGER  ADAMS 

in  300  cc.  of  dry  ether  was  treated  with  20  g.  of  freshly  fused  and  powdered  zinc  chloride. 
The  mixture  was  cooled  in  an  ice-bath  and  dry  hydrogen  chloride  passed  in  until  the 
ether  was  saturated.  Upon  standing  overnight,  a  sirupy  mass  deposited.  The  ether 
was  decanted  and  the  residue  treated  with  30  cc.  of  water.  After  standing  for  15  hours, 
a  small  amount  of  solid  and  some  liquid  separated.  The  oil  (10  g.)  was  filtered  from  the 
solid  (3.5  g.)  by  the  use  of  suction.  The  solid,  upon  crystallization  from  water,  was 
obtained  pure  and  melted  at  138-139.5°.  It  proved  to  be  /9-(2-hydroxy-4-methoxy- 
phenyl)propionic  acid. 

Analyses.     Subs.,  0.3819:   CO2,  0.8604;  H2O,  0.1982.     Calc.  for  Ci2Hi0O4:   C,  61.2; 
H,  6.1.     Found:   C,  61.4;  H,  5.8. 


/3-(2-Hydroxy-4-methoxyph'enyl)propionicAcidLactone, 


\/\C/ 

H2 

The  oil  obtained  by  filtration  of  the  0-(2-hydroxy-4-methoxyphenyl)propionic  acid  was 
insoluble  in  cold  sodium  hydroxide  solution,  but  dissolved  on  heating.  It  could  not  be 
distilled  under  a  pressure  of  6  mm.  It  was  found,  however,  that  by  boiling  the  oil  with 
sodium  carbonate  solution  for  some  time,  and  acidifying  the  resulting  solution,  it  was 
converted  completely  into  /3-(2-hydroxy-4-methoxyphenyl)propionic  acid,  which  melted 
at  138-139°.  The  same  oil  was  produced  by  heating  /3-(2-hydroxy-4-methoxyphenyl)- 
propionic  acid  in  an  oven  at  132°  and  was,  therefore,  without  doubt  /3-(2-hydroxy-4- 
methoxyphenyl)propionic  acid  lactone. 

CH8C/\OH 
/3-(2-Hydroxy-4-methoxyphenyl)propionitrile,  .—The    ether 

solution  which  was  decanted  from  the  original  reaction  mixture  between  /3-chloro- 
propionitrile  and  resorcinol  monomethyl  ether  was  evaporated  in  a  vacuum  and  about 
12  g.  of  unchanged  /3-chloro-propionitrile  recovered.  A  higher-boiling  fraction  of  re- 
sorcinol monomethyl  ether  (21  g.)  was  also  obtained.  The  residue  in  the  flask  solidified 
on  cooling.  It  was  purified  by  crystallization  from  dil.  alcohol  and  then  melted  at  126.5- 
127.5°.  Analysis  showed  it  to  be  /3-(2-hydroxy-4-methoxyphenyl)propionitrile. 

Analyses.'  Subs.,  0.3718:  N2,  27.2  cc.  (28°  and  749  mm.).  Subs.,  0.2968:  CO2, 
0.7353.  Calc.  for  Ci0Hu02N:  C,  67.6;  H,  6.2;  N,  7.9.  Found:  C,  67.5;  H,  6.5;  N,  8.0. 

It  was  insoluble  in  sodium  carbonate  but  soluble  in  sodium  hydroxide  solution  and 
was  recovered  unchanged  upon  acidification.  When  it  was  boiled  with  alkali  ammonia 
was  evolved  and,  after  acidification,  /3-(2-hydroxy-4-methoxyphenyl)propionic  acid  was 
obtained. 

HO/NoH 

-y-(2,4-Dihydroxyphenyl)butvric  Acid,  .  —  A  mixture  of 

1X/JCH2CH2CH2C02H 

64  g.  of  resorcinol  and  60  g.  of  7-chloro-butyronitrile  was  dissolved  in  400  cc.  of  dry 
ether;  30  g.  of  fused  and  powdered  zinc  chloride  was  added,  and  dry  hydrogen  chloride 
was  passed  in  rapidly  for  2  hours.  The  flask  was  then  sealed,  and  allowed  to  stand. 
Hydrogen  chloride  was  passed  in  for  1  hour  on  each  of  2  successive  days,  and  the 
flask  was  allowed  to  remain  sealed  for  4  more  days.  By  that  time  the  oil  which  had 
separated  had  entirely  crystallized.  The  ether  was  filtered  and  the  solid  dissolved  in 
250  cc.  of  water,  heated  for  3  hours  on  a  steam-bath  and  then  cooled.  The  crystals 
which  slowly  formed  were  filtered  and  dried,  and  weighed  24.5  g.  (20.8%). 


CONDENSATION  OF  NITRILES  AND  PHENOLS  2329 

For  purification,  10  g.  of  the  product  was  dissolved  in  57  cc.  of  boiling  water,  ancj 
filtered  hot.  An  oil  separated,  which  when  cooled  and  stirred,  solidified.  The  weight 
recovered  was  9.5  g.,  and  the  substance  melted  at  89-99°.  Repeated  crystallization  did 
not  make  this  melting  point  sharper,  but  after  the  melt  had  been  allowed  to  solidify,  it 
reinelted  at  118-119°.  This  indicated  that  the  low-melting  product  contained  water 
of  crystallization,  and  a  moisture  determination  confirmed  this. 

Analyses.  Subs.,  0.7322,  0.5297:  H2O,  0.0655,  0.0471.  Calc.  for  CnH12O4.H2O: 
H2O,  8.4.  Found:  H2O,  8.94,  8.89. 

The  anhydrous  product  was  readily  crystallized  from  benzene  hi  the  form  of  color- 
less plates,  and  melted  at  118.5-119°. 

Analyses.  Subs.,  0.1628:  CO2,  0.3640;  H2O,  0.0865.  Subs.,  0.1491:  9.98  cc.  of 
0.0717  N  NaOH.  Calc.  for  Ci0H12O4:  C,  61.22;  H,  6.12;  neut.  equiv.,  198.  Found: 
C,  60.96;  H,  5.95;  neut.  equiv.,  208. 

A  portion  of  the  anhydrous  y-  (2,4-  dihydroxyphenyl)  butyric  acid  was  heated  in  an 
oven  at  133-134°  for  0.5  hour.  The  solid  melted  to  a  red  liquid  which  solidified  on  cool- 
ing and,  upon  recrystallization  from  benzene,  proved  to  be  unchanged  starting  material. 
Therefore,  no  lactone  of  this  acid  formed  under  the  same  conditions  as  were  used  with 
/3-  (2,4-dihydroxyphenyl)propionic  acid. 

In  order  to  study  the  intermediate  products  formed  in  the  condensation  of  resorcinol 
and  7-chloro-butyronitrile,  another  condensation  was  made  under  the  same  conditions 
as  are  given  above.  The  initial  crystalline  .reaction  product  was  treated  with  water, 
warmed  to  50°,  cooled,  and  the  solution  partly  neutralized  with  dil.  sodium  carbonate 
solution.  The  oil  which  formed  solidified,  and  the  resulting  substance  was  filtered  and 
washed  with  dil.  hydrochloric  acid.  It  was  a  white  powder,  melting  at  214—216°,  but 
when  it  was  washed  with  water  the  color  changed  to  a  canary-yellow,  and  the  melting 
point  dropped  to  190-192°.  When  the  yellow  compound  was  washed  with  methyl  al- 
cohol saturated  with  hydrogen  chloride,  it  became  white,  and  the  original  higher-melting 
product  resulted. 

The  wash  waters,  on  standing,  gave  a  small  amount  of  white  solid  which  proved  to 
be  /3-(2,4-dihydroxyphenyl) butyric  acid. 


/3-(2,4-Dihydroxy-6-methylphenyl)propionic  Acid  Lactone, 


Five  g.  of  orcinol  and  5  g.  of  /3-chloro-propionitrile  were  dissolved  in  100  cc.  of  dry  ether, 
and  5  g.  of  freshly  fused  and  powdered  zinc  chloride  added.  The  ether  was  cooled  in  an 
ice-bath,  and  dry  hydrogen  chloride  passed  in  until  the  ether  was  saturated.  A  white 
solid  formed  overnight,  and  after  10  hours  there  appeared  to  be  no  more  deposit  forming. 
The  ether  was  decanted,  the  solid  washed  with  dry  ether,  treated  with  20  cc.  of  water, 
warmed  to  50°  and  cooled  in  an  ice-bath.  The  oil  which  formed  could  not  be  made  to 
crystallize,  even  when  dry  toluene  was  used  as  the  solvent.  The  heating  was,  therefore, 
continued  and  ammonia  was  added  until  the  solution  was  just  neutral.  After  1  hour  the 
solution  was  boiled  with  bone  black,  filtered  and  acidified  with  hydrochloric  acid.  On 
cooling,  an  oil  layer  separated  which  slowly  solidified  on  standing.  This  was  filtered  and 
dried,  when  it  weighed  4  g.  and  melted  at  125-133°.  It  was  recrystallized  from  hot 
dil.  methyl  alcohol,  4  g.  dissolving  in  90  cc.  of  10%  alcohol;  1.7  g.  of  solid  was  obtained 
melting  at  140-141 .5°.  The  remainder  of  the  product  came  out  as  an  oil  which  solidified 
after  2  weeks'  standing.  This  was  again  boiled  with  bone  black  and  filtered,  when  0.2  g. 
more  of  solid  was  obtained. 


2330  WILSON  D.  LANGLEY  WITH  ROGER  ADAMS 

Analyses.  Subs.,  0.3923:  CO2,  0.9641;  H2O,  0.1934.  Calc.  for  C10H10O,:  C,  67.4; 
H,5.6.  Found:  C,  67.01  ;H,  5.5. 

This  product  was  difficultly  soluble  in  hot  water,  but  readily  soluble  in  hot  alkali. 
Since  the  lactone  was  obtained  on  acidification  of  the  alkaline  solution,  the  acid  is  not 
stable  under  ordinary  conditions.  The  same  product  was  obtained  in  a  purer  form  from 
acrylic  nitrile,  3.6  g.  being  obtained  from  5  g.  of  orcinol  and  2.3  g.  of  acrylic  nitrile. 


j8-(2,4,6-TrihydroxyphenyI)propionic  Acid    Lactone,  QH(J!    . — Five 

<=H, 

g.  of  pure  phloroglucinol,  dried  at  120°  to  free  it  from  water  of  crystallization,  and 
5  g.  of  /3-chloro-propionitrile  were  dissolved  in  100  cc.  of  dry  ether,  and  4  g.  of  powdered 
zinc  chloride  was  added.  The  flask  was  cooled  and  dry  hydrogen  chloride  was  passed  in 
until  the  solution  was  saturated.  The  mixture  was  allowed  to  stand  for  20  hours,  the 
ether  was  decanted  from  the  solid  which  had  separated  and  the  residue  washed  with  dry 
ether.  It  was  then  treated  with  20  cc.  of  water,  warmed  to  about  40°  for  5  minutes,  and 
cooled  with  ice.  No  oil  layer  separated.  After  standing  for  24  hours,  the  water  solution 
was  extracted  twice  with  50  cc.  portions  of  butyl  alcohol,  the  butyl  alcohol  in  turn 
washed  with  water,  and  the  wash  water  extracted  with  fresh  butyl  alcohol.  The 
butyl  alcohol  was  distilled  in  a  vacuum  and  10-12  g.  of  dark  brown  liquid  was  obtained. 
This  was  taken  up  in  150  cc.  of  boiling  water,  heated  until  all  of  the  butyl  alcohol  had 
been  removed,  treated  with  bone  black,  and  filtered.  The  filtrate  was  light  brown,  and 
from  it  there  separated  about  5  g.  of  a  viscous  oil.  This  could  not  be  obtained  crystal- 
line. It  changed  to  a  glassy  mass  on  standing  for  a  long  time  in  a  desiccator  over  sul- 
furic  acid,  and  could  not  be  crystallized  from  anhydrous  solvents. 

This -oil  decomposed  carbonate  solutions  when  heated,  and  went  into  solution. 
On  acidification,  the  oil  formed  again.  Attempts  were  made  to  prepare  derivatives  of 
the  oil,  such  as  those  with  phenyl-isocyanate,  diphenyl-carbamine  chloride,  and  the 
acetate  and  benzoate.  None  of  these  could  be  obtained  in  crystalline  form.  Acrylic 
nitrile  gave  the  same  type  of  oil,  which  possessed  all  the  properties  of  that  obtained 
above. 

Summary 

1.  /3-Chloro-propionitrile  condenses  with  resorcinol  in  the  presence 
of  anhydrous  zinc  chloride,  hydrogen  chloride  and  dry  ether  to  give  a 
crystalline  intermediate  product  which  hydrolyzesto  form  /3-(2,4-dihydroxy- 
phenyl)propionic  acid. 

2.  By  a  similar  procedure  /3-chloro-propionitrile  and  resorcinol-mono- 
methyl  ether  give  a  mixture  of  j3-(2,4-dihydroxyphenyl)propionitrile  and 
the  corresponding  acid  and  lactone.     From  orcinol  and  phloroglucinol 
intermediate  products  are  formed  which  give  on  hydrolysis  the  analogous 
lactones. 

3.  7-Chloro-butyronitrile    and    resorcinol    condense    under    similar 
conditions  to  give  a  product  which  hydrolyzes  to  form  7-(2,4-dihydroxy- 
phenyl)butyrfr  acid. 

4.  The  mechanism  by  which  the  above  products  are  formed  is  discussed. 
URBANA,  ILLINOIS 


VITA 

The  writer  was  born  in  Charleston,  South  Carolina,  on  January 
7,  1895.  At  the  age  of  nine  years,  he  moved  to  Schenectady,  New  York, 
where  he  completed  his  grammar  and  high  school  education.  He 
entered  Wesleyan  University,  Middletown,  Connecticut,  in  the  class  of 
1918,  and  secured  the  degree  of  Bachelor  of  Science  in  that  year.  He 
completed  one  year  of  graduate  study  at  the  same  institution,  and  re- 
ceived the  degree  of  Master  of  Science  in  1919.  He  has  since  been 
a  graduate  student  at  the  University  of  Illinois. 

His  teaching  appointments  have  been  as  follows : 

1919-20     Graduate  Assistant  in  Chemistry 

1920-21     Assistant  in  Chemistry 

1921-.22     (first  semester)     Graduate  Assistant  in  Chemistry. 


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